Genomic variations in the MMP-1 promoter influence estrogen receptor beta mediated activity in mechanically activated environments

Matrix metalloproteinase-1 (MMP-1) contributes to pathological degradation of connective tissues in osteoporosis and arthritis. Previously, a single nucleotide polymorphism (SNP) was described in the MMP-1 promoter consisting of a deletion/insertion (1G/2G) of a guanine nucleotide. The 2G allele enhances MMP-1 expression and is associated with increased risk of cancer metastasis, but has not been examined with respect to connective tissue diseases. This study examined the effect of the 1G/2G SNP on MMP-1 promoter responses to a variety of stimuli that play a role in the pathological expression of MMP-1 in connective tissue diseases, namely mechanical forces, sex hormones and cytokines. The 2G allele enhanced the effects of shear force, IL-1beta, and ERbeta on promoter activity in mechanoresponsive synovial cells and enabled interactions between these signaling pathways. The 1G/2G SNP genotype may affect the MMP-1 response to stimuli in vivo and contribute to the risk or progression of connective tissue diseases.